Human diabetes, a disease in which a major indicator is an elevated blood glucose level, is generally believed to result from low insulin levels and elevated glucagon levels. However, hyperglycemia in non-insulin dependent diabetes (both in non-obese and obese patients), has been shown in the presence of both elevated glucagon and insulin levels.
Insulin is known to rapidly decrease blood glucose levels, while glucagon (a polypeptide hormone twenty-nine amino acid residues in length) is believed to contribute to elevated blood glucose levels by binding to liver membrane receptors, and thereby triggering glycogenolysis which results in the production of glucose. Elevated glucagon levels are also associated with a substantial increase in gluconeogenesis.
The binding of glucagon to its cellular receptor triggers the stimulation of adenylate cyclase activity leading to the production of cyclic AMP (cAMP), and results in an increase in glycogenolysis and gluconeogenesis and the accompanying release of glucose. In addition to cAMP-stimulated gluconeogenesis and glycogenolysis, other pathways have been suggested for the glucagon-stimulated production of glucose through glycogeaolysis and gluconeogenesis. For example, the binding of glucagon to its cellular receptor activates protein kinase C leading to the formation of inositol triphosphate, which acts as a signal for the release of free calcium sequestered in the endoplasmic recticulum (Pittner and Fain, Biochem. J. 277:371-378, 1991). Furthermore, Wakelam et al. (Nature 323:68-71, 1986) suggest that the stimulation of inositol triphosphate production provides a cAMP-independent pathway for gluconeogenesis and glycogenolysis.
While stable control of insulin levels is difficult to achieve, treatment for insulin-dependent diabetes and some non-insulin dependent diabetes has been achieved through a combination of controlled diet and periodic doses of exogenous insulin. It is believed that the therapeutic use of glucagon antagonists will inhibit glycogenolysis and help to lower and/or maintain blood glucose levels in diabetics by inhibiting glucagon-induced glucose production.
Accordingly, it is an object of the present invention to provide glucagon antagonists, as well as methods for the production thereof. It is a further object of this invention to provide methods of formulating and administering glucagon antagonists to treat disease states associated with elevated glucose levels. The present invention fulfills these objectives, and provides further related advantages.